Clinical efficacy and safety of acupuncture combined with statin in dyslipidemia: A meta-analysis and system review

Background: This study aims to systematically evaluate the clinical efficacy and safety of acupuncture in combination with statin therapy compared to statin monotherapy for the treatment of dyslipidemia. Methods: A comprehensive search for relevant randomized controlled trials assessing the clinical efficacy of acupuncture and statin combination in the treatment of dyslipidemia was conducted. Databases including PubMed, EMbase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc, Wanfang database, and China Science and Technology Journal Database were searched up to October 27, 2023. Results: Sixteen Chinese-language studies involving a total of 1333 subjects were included for analysis. The meta-analysis revealed that the total effective rate of acupuncture combined with statin was significantly higher than that of statin alone (odds ratios = 3.32, 95% confidence intervals [CI] = 2.33 to 4.72). Furthermore, the combination of acupuncture with statin treatment resulted in a significant reduction in triglyceride levels (mean differences [MD] = −0.72 mmol/L, 95% CI = −1.05 to −0.4), total cholesterol levels (MD = −0.79 mmol/L, 95% CI = −1.07 to −0.51), low-density lipoprotein cholesterol levels (MD = −0.61 mmol/L, 95% CI = −0.95 to −0.27) and traditional Chinese medicine syndrome integral (MD = −1.32, 95% CI = −1.75 to −0.89), compared to statin treatment alone. Additionally, the high-density lipoprotein cholesterol level was higher in the combined acupuncture and statin treatment group than in the statin treatment alone group (MD = 0.44 mmol/L, 95% CI = 0.09 to 0.79). Notably, the rate of adverse reactions reported with combined acupuncture and statin treatment was lower than that with statin therapy alone. Conclusion: Our findings support the potential of acupuncture combined with statin as a viable clinical treatment option for dyslipidemia. However, it is important to note that current research on the mechanism of acupuncture for lipid-lowering has not yielded definitive results, and there are inherent biases in the conducted clinical studies.


Introduction
Dyslipidemia, characterized by elevated triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and reduced high-density lipoprotein cholesterol (HDL-C), is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), presenting a substantial challenge in developing countries. [1]Based on a recent study published in the journal Nature, [2] it has been observed that developing countries in East Asia, Southeast Asia, and Oceania have witnessed a substantial increase in non-HDL-C levels over the past 4 decades, with the highest surge recorded at 0.88 mmol/L.Notably, China has demonstrated one of the most rapid escalations in non-HDL-C levels globally, with the age-standardized average non-HDL-C level for Chinese men rising from 2.77 mmol/L in 1980 to 3.38 mmol/L in 2018. [2]These trends have also led to a significant global burden, with approximately 3.9 million people dying from hypercholesterolemia each year, half of whom are in China and other Southeast Asian countries. [2]hile health care policies and targeted LDL-C lowering drugs The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.a  have shown promise in reducing ASCVD burden, challenges persist. [3]Statins, the primary medication for lipid regulation, have demonstrated significant clinical lipid-lowering effects.However, issues such as statin intolerance, failure to achieve desired lipid-lowering effects at moderate intensity, and an increased risk of new-onset diabetes at high intensity remain prevalent.Although new lipid-lowering drugs like proprotein convertase subtilisin/kexin type 9 inhibitors offer additional lipid adjustment potential, their high cost impedes widespread adoption in developing countries.Acupuncture, as a traditional Chinese medicine (TCM) treatment, has garnered attention for its clinical efficacy in recent years.It has been utilized either independently or in combination with statin for dyslipidemia treatment in TCM institutions.Therefore, this meta-analysis aims to provide evidence-based insights into the efficacy and safety of acupuncture combined with statin in managing dyslipidemia.

Inclusion and exclusion criteria
Participant inclusion criteria: Our study does not impose restrictions based on age, gender, or source of cases for participants.However, participants must have been diagnosed with primary dyslipidemia in accordance with the Chinese guidelines. [4]xclusion criteria encompass individuals with other serious diseases or complications, as well as those with unstable vital signs.Pregnant women are also ineligible for participation.Intervention: The study aimed to compare the effects of statin therapy alone with those of combined statin and acupuncture treatment.The control group received primarily statin therapy, while the intervention group underwent acupuncture therapy, including electroacupuncture, manual acupuncture, auricular acupuncture, and warm acupuncture, in conjunction with an equivalent statin dosage.Acupoint injection and acupoint embedding were excluded to ensure the specific intervention effect of acupuncture combined with statin.Outcome Measures: The primary outcome measure focused on the total effective rate, as per the Clinical Guiding Principles of New Chinese Medicine. [5]Secondary outcomes encompassed serum lipids levels, adverse reactions, and TCM syndrome integral, with standards based on Clinical Guiding Principles of New Chinese Medicine. [5]Study Design: The eligibility criteria were defined as randomized controlled trials (RCTs) employing a double-blind, single-blind, or non-blind design.Trials were excluded based on the following criteria: duplicate publication, unavailability of full-text access, and inability to obtain test data.Heng 2020 [14] 45

Data selection and extraction
The initial literature screening was independently conducted by 2 researchers (X.L. and K.C.).The process involved an initial

Quality assessment
Once a decision was made regarding the inclusion of literature in the analysis, full articles were assessed using the Cochrane Risk of Bias tool. [6]In cases of disagreement, efforts were made to reach a consensus, and if necessary, a third party (F.C.) was consulted.
The Cochrane Risk of Bias tool comprises 6 individual domains, including: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias.Each domain was categorized as presenting a low risk of bias, high risk of bias, or unclear risk of bias.

Statistical analyses
All data analysis in this study was conducted using R version 4.1.2(https://www.r-project.org/)software.Binary outcomes  were summarized using odds ratios with 95% confidence intervals (CI), while continuous outcomes were presented as weighted mean differences (MD) with 95% CI.Heterogeneity was evaluated using the chi-square test and the Higgins I 2 test.Publication bias was assessed using funnel plots, Begg's test, and Egger's test, calculated with R software.To address potential outcome heterogeneity, sensitivity analyses were performed through subgroup analyses based on mean age, disease duration, and intervention duration, as well as through case-by-case exclusions.

Ethics approval/institutional review board
This type of study is a meta-analysis, so it is exempt from ethical approval.

Search results
The for Systematic Reviews and Meta-Analyses guidelines, [7] is available in Figure 1.

Characteristics of included studies
Selected characteristics of the included studies are reported in Table 1.

Quality assessment
We evaluated the methodological quality of the included literature according to the Cochrane handbook. [6]No selective reports were found in the 16 included RCTS.There were 15 studies that reported complete results, 14 of which used randomized methods, but the details were unclear; Only 4 of them specifically described the generation of random sequences, 1 study implemented the single-blind method, 2 studies demonstrated allocation concealment, and 16 other biases were not clear.See Figure 2 for details.

Therapeutic evaluation
3.4.1.Total effective rate.Eleven studies (n = 896) reported the total effective rate for acupuncture combined with statin in the treatment of dyslipidemia.The heterogeneity test results indicated homogeneity among the studies (P = .64,I 2 = 0%), and therefore, the fixed-effect model was utilized (Fig. 3).The pooled odds ratio value was 3.12, with a 95% CI of 2.17 to 4.48, demonstrating that acupuncture combined with statin was more effective than statin alone.

TG level.
Fifteen studies (n = 1228) investigated the impact of intervention on TG levels.The results revealed significant heterogeneity (I 2 = 78%, P < .01),leading us to employ a random effects model for analysis.The pooled MD was −0.79 mmol/L, with a 95% CI of −1.07 to −0.51, indicating that acupuncture combined with statin treatment effectively reduces TG levels, as depicted in Figure 4. Subgroup analysis results, illustrated in Figures 5 and 6, demonstrated a reduction in heterogeneity among individuals with a mean age less than 60 years or an average disease duration of less than or equal to 30 days.Notably, significant reduction in heterogeneity was observed upon excluding one or both of the studies by Heng et al [14] and You et al [21] (Figs. 7 and 8).Consequently, it is important to acknowledge that the heterogeneity may have originated from the inclusion of low-quality studies in the analysis.

TC level.
Sixteen studies (n = 1328) assessed TC level following intervention.The results exhibited significant heterogeneity (I 2 = 85%, P < .01),prompting the utilization of a random effects model for analysis.The pooled MD was −0.72 mmol/L, with a 95% CI was −1.05 to −0.4, as depicted in Figure 9, indicating a moderate effect favoring acupuncture combined with statin therapy.Given the substantial heterogeneity in the results, we conducted subgroup analyses based on mean age, disease duration, and time of intervention, as well as sensitivity analysis involving one-by-one exclusion.
As illustrated in Figure 10, the subgroup analysis revealed a reduction in heterogeneity only among patients aged 60 years or older (70% heterogeneity).However, no significant reduction in heterogeneity was observed in the one-by-one exclusion method.and 55% in the group with a duration of intervention of less than or equal to 30 days.Upon excluding studies by You et al [21] and Tang, [15] the MD was 0.42 mmol/L, with a 95% CI of 0.08 to 0.22, and heterogeneity declined significantly to 64% (Fig. 15).

Low-density lipoprotein cholesterol.
Sixteen studies (n = 1328) investigated the impact of intervention on LDL-C levels.The results demonstrated significant heterogeneity (I 2 = 86%, P < .01),leading to the use of a random effects model for analysis.The pooled MD was −0.61 mmol/L, with a 95% CI of −0.95 to −0.27, as depicted in Figure 16, indicating a favorable effect of acupuncture combined with statin treatment in reducing LDL-C levels.In the subgroup analysis, as illustrated in Figures 17 to 19, heterogeneity was reduced to 72% in the group with a disease duration of less than 3 years, 0% in the group with an age of 60 years or older, and 46% in the group with a duration of intervention of less than or equal to 30 days.Upon excluding studies by You et al [21] and Heng et al, [14] the MD was −0.41, with a 95% CI of −0.62 to −0.20, and the heterogeneity decreased to 68% (Fig. 20).

Adverse reactions.
In the included studies, a total of 7 articles provided data on adverse reaction outcomes, with the control group receiving statin intervention.Chen et al [9] reported 4 cases (6.16%) of adverse reactions in the combined acupuncture group and 23 cases (46.93%) in the statin group.The incidence of adverse reactions in the combined acupuncture group was significantly lower than that in the statin group (P < .05).Wang et al [19] reported 5 cases (10%) of adverse reactions in the combined acupuncture group and 3 cases (6%) in the statin group.Although the incidence of adverse reactions in the combined acupuncture group was lower than that in the statin group, the difference was not statistically significant (P > .05).Shuhong et al [17] reported 1 case (2.08%) of adverse reaction in the combined acupuncture group and 8 cases (16.67%) in the statin group.The incidence of adverse reactions in the combined acupuncture group was significantly lower than that in the statin group (P = .036).The remaining 4 articles reported no adverse reactions in either the acupuncture combined group or the statin group alone.Therefore, based on the available evidence, it can be inferred that the rate of adverse reactions in the acupuncture combined with statin group is generally lower than that in the statin group alone.

TCM syndrome integral.
Five studies comprising a total of 450 participants assessed the effectiveness of combined acupuncture and statin therapy for TCM syndrome integral.The pooled MD was −1.32, with a 95% CI of −1.75 to −0.89 (P < .01)(Fig. 21).These findings suggest that the combination of acupuncture and statin therapy in the management of dyslipidemia may lead to a further reduction in the TCM syndrome integral of patients, indicating a more favorable treatment outcome compared to statin monotherapy.

Publication bias
We believe that there may be some subjectivity in the interpretation of Funnel plot (Fig. 22), so we conducted Begg test and Egger test on the above 6 outcome indicators on this basis.The operational results are shown in Table 2.The test results of all 6 outcome indicators are greater than 0.05.There was no suggested evidence of publication bias at post-intervention.

Discussion
Dyslipidemia is one of the important independent risk factors for disabling and fatal atherosclerotic diseases such as myocardial infarction and stroke. [24]Prolonged inadequate control of serum lipids can lead to severe adverse outcomes.A mendelian randomization study, [25] featured in the New England Journal of Medicine, revealed that for every 10 milligrams per deciliter reduction in LDL-C level, the risk of cardiovascular events diminished by 17.6% (ACLY score) or 16.4% (HMGCR score).
Additionally, a large-scale prospective clinical meta-analysis demonstrated a substantial reduction in ASCVD risk with the decrease of non-high-density lipoprotein cholesterol. [26]Data from 6 community-based cohorts [27] exhibited an inverse and linear correlation between HDL-C and coronary heart disease risk up to a threshold of ≤90 mg/dL.A comprehensive 19-year Chinese cohort study revealed a notable increase in ASCVD risk with rising TG levels, with serum TG level independently and positively linked to ASCVD risk. [28]Effective dyslipidemia management can lead to reduced hospitalization rates, lower fatality rates, and improved survival rates. [24]gure 13.Subgroup analysis of HDL-C according to mean age.HDL-C = high-density lipoprotein cholesterol.However, the use of statins as the primary medication for lipid reduction has limitations.A meta-analysis [29] revealed that long-term statin use resulted in only a 4% to 10% increase in HDL-C.High-intensity rosuvastatin (20 mg/d) was found to increase HDL-C by only 6.1%. [30]Moreover, research by Preiss et al [31] indicated that intensive statin treatment significantly raised the risk of new-onset diabetes.Statins have limited effects in reducing TG, and their combination with fibrates may increase the risk of liver damage, myositis, and myopathy due to similar metabolic pathways.Furthermore, statin intolerance also poses challenges for some dyslipidemia patients and medical staff. [32]ur study demonstrates that compared to using statin alone, the combined use of acupuncture and statin yields a significant therapeutic effect (total effective rate odds ratio value = 3.12, 95% CI = 2.17   The combination therapy also exhibited a favorable safety profile, with a lower incidence of adverse reactions compared to using statin alone.This indicates that acupuncture combined with statin is a safer approach for dyslipidemia treatment.However, our study also acknowledges certain limitations.The heterogeneity across the included studies was high, likely  due to differences in patient characteristics, treatment regimens, and study methodologies.Additionally, the sample size of the studies was relatively small, warranting the need for larger, multi-center randomized controlled trials in the future.Standardized research and testing methods, as well as the establishment of effective evaluation systems, are essential to improve the quality and reliability of findings in this field.Furthermore, the mechanism of action of acupuncture in treating dyslipidemia is not fully understood, and the existing efficacy evaluation systems may not fully capture the benefits of TCM treatments.Future research should focus on elucidating the mechanisms of acupuncture and combined treatments, as well as developing a unified evaluation system for the therapeutic effects of acupuncture and moxibustion on dyslipidemia.
In conclusion, while statins remain a cornerstone of dyslipidemia management, the potential of acupuncture and moxibustion therapy as a complementary and alternative treatment warrants further investigation.Larger clinical trials and mechanistic studies are needed to fully explore the potential of this approach and establish its place in the management of dyslipidemia.The development of standardized research and testing methods, as well as effective evaluation systems, is crucial to improving the quality and reliability of findings in this field.

Figure 1 .
Figure 1.PRISMA diagram of the search strategy.PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 3 .
Figure 3. Meta analysis of the total effective rate.

Figure 5 .
Figure 5. Subgroup analysis of TG according to mean age.TG = triglyceride.

Figure 6 .
Figure 6.Subgroup analysis of TG according to intervention time.TG = triglyceride.

Figure 8 .
Figure 8. Sensitivity analysis of TG excluded JIN and Hong's study.TG = triglyceride.

Figure 9 .
Figure 9. Meta analysis of TC level.TC = total cholesterol.

Figure 12 .
Figure 12.Subgroup analysis of HDL-C according to duration of the disease.HDL-C = high-density lipoprotein cholesterol.

Figure 14 .
Figure 14.Subgroup analysis of HDL-C according to intervention time.HDL-C = high-density lipoprotein cholesterol.

Figure 15 .
Figure 15.Sensitivity analysis of HDL-C excluded Hong and Zhi's study.HDL-C = high-density lipoprotein cholesterol.

Figure 17 .
Figure 17.Subgroup analysis of LDL-C according to mean age.LDL-C = low-density lipoprotein cholesterol.

Figure 20 .
Figure 20.Sensitivity analysis of excluded JIN and Hong's study.LDL-C = low-density lipoprotein cholesterol.

Figure 19 .
Figure 19.Subgroup analysis of LDL-C according to intervention time.LDL-C = low-density lipoprotein cholesterol.

Figure 21 .
Figure 21.Meta analysis of TCM syndrome integral.TCM = traditional Chinese medicine.
Department of Science and Education, Foshan Shunde District Traditional Chinese Medicine Hospital: Guangzhou University of Traditional Chinese Medicine ShunDe Traditional Chinese Medicine Hospital, FoShan, China, b Clinical Medical College of Acupuncture Moxibustion, Guangzhou University of Chinese Medicine (Guangzhou University of Chinese Medicine Equivalent Mechanics Applicants for Master's Degree), Guangzhou, China, c Department of Preventive Treatment of Disease, Foshan Shunde District Traditional Chinese Medicine Hospital: Guangzhou University of Traditional Chinese Medicine, FoShan, China.

Table 1
Characteristics of included studies.
initial search strategy identified 1205 studies, with no clinical registration trials and 1205 published articles (PubMed: 38, Embase: 52, Cochrane Library: 60, Web of Science: 26, China Biology Medicine disc: 154, China National Knowledge Infrastructure: 433, Wan Fang database: 220, China Science and Technology Journal Database: 222).After manually reviewing the literature, 596 duplicate articles were excluded.Secondly, 567 articles were excluded by reading the title and abstract.Subsequently, after full-text review, 21 articles were further excluded for reasons such as non-RCT study design, absence of a statin control group, missing or unavailable data, lack of peer review, or absence of serum lipid outcome data.Ultimately, 16 articles were included in the final analysis.A diagram illustrating the search strategy, following the Preferred Reporting Items